MicroRNA-511-3p Mediated Modulation of the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Controls LPS-Induced Inflammatory Responses in Human Monocyte Derived DCs

Awuah, Dennis; Ruisinger, Alisa; Alobaid, Meshal; Mbadugha, Chidimma; Ghaemmaghami, Amir M.

Abstract

Abstract: The peroxisome proliferator-activated receptor gamma (PPAR) is a ligand-activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR 511) has also emerged as a key player in controlling TLR4-mediated signalling and in regulating the function of DCs. Interestingly, PPAR
has been previously highlighted as a putative target of miR-511 activity; however, the link between miR-511 and PPAR and its influence on human DC function within the context of LPS-induced
inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that knockdown or overexpression of miR-511-3p inversely correlates with PPAR mRNA levels and affects its transcriptional activity following treatment with rosiglitazone (RSG; PPAR
agonist), in the presence or absence of LPS. Additionally, we show that PPAR-mediated suppression of DC activation and pro-inflammatory cytokine production in miR-511-3p knockdown DCs is abrogated following overexpression of miR-511-3p. Lastly, PPAR
activation suppressed LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. Our data thus suggests that PPAR-induced modulation of DC phenotype and function is influenced by miR-511 3p expression, which may serve as a potential therapeutic target against inflammatory diseases.

• Journal Article Type: Article
• Acceptance Date: Jan 11, 2022
• Online Publication Date: Jan 14, 2022
• Publication Date: Jan 14, 2022
• Deposit Date: Feb 17, 2022
• Publicly Available Date: Feb 17, 2022
• Journal: Immuno
• Print ISSN: 2673-5601
• Electronic ISSN: 2673-5601
• Publisher: MDPI AG
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 1
• Pages: 104-117
• DOI: https://doi.org/10.3390/immuno2010008
• Keywords: dendritic cells; miR-511-3p; RNAi; PPAR ; inflammation; indoleamine 2,3 dioxygenase; immune modulation
• Public URL: https://nottingham-repository.worktribe.com/output/7471698
• Publisher URL: https://www.mdpi.com/2673-5601/2/1/8